The majority of multiple myeloma (MM) patients will initially respond to standard chemotherapy. However, eventually relapse of the disease, associated with a multi-drug resistant phenotype, contributes to poor clinical outcomes. Our laboratory has recently discovered that a d-amino acid containing peptide, HYD1, blocks adhesion of myeloma cells to extracellular matrices and induces necrotic cell death. Importantly, ex-vivo HYD1 demonstrates increased potency in MM cells obtained from relapsed patients compared to newly diagnosed, indicating that this novel class of compounds may be an effective strategy for the treatment of relapsed myeloma patients. We have recently cyclized the linear HYD1 peptide which we refer to as cHYD1 binds. cHYD1 binds to the extracellular domain of recombinant CD44 with a KD value of 5 nM. Furthermore, biotin conjugated peptide pulls down a CD44/VLA-4 containing complex using membrane extracts obtained from MM cell lines. CD44 is known to regulate integrin mediated adhesion, trafficking of leukocytes, survival, and differentiation. We propose that the dual function of blocking matrix mediated cell adhesion and inducing cell death provides evidence that cHYD1 is an attractive novel class of anti-cancer agents. Furthermore, we hypothesize, based on the biology of the target, that cHYD1 will disrupt the MM niche. It is well known that the MM niche is critical for disease progression and emergence of drug resistance and agents that disrupt the niche are needed to improve standard therapy. The goal of specific aim 1 of this proposal will be to determine the efficacy of cHYD1 in combination with bortezomib, using immune competent in vivo models. The goal of specific aim 2 will be to determine the effect of cHYD1 on disrupting specific components of the MM niche. PUBLIC HEALTH RELEVANCE: Clinical outcomes strongly support the need for the development of novel strategies for the treatment of this deadly disease. To this end this proposal will determine whether the cyclized peptide referred to as cHYD1 is an attractive strategy to combine with standard therapy for the treatment of myeloma.